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Pre-Implantation Genetic Diagnosis (PGD) and Pre-Implantation Genetic Screening (PGS)

The Family Beginnings IVF laboratory performs embryo biopsy for PGD and PGS, helping many patients that may be at risk of having abnormal embryos and offspring. PGD refers to the diagnosis of disease by embryo biopsy before implantation. The parents may be carriers of a condition, like Cystic Fibrosis. They may have a child that is affected and wish to have early diagnosis in future pregnancies.

PGS refers to the screening of the embryo chromosomes in search of abnormalities such as Down’s Syndrome. Parents are unaffected but may be at high risk for having an affected child due, for instance, increased maternal age, recurrent miscarriage, and/or multiple failed IVF cycles. We are also able to determine the sex of the embryo with PGD/PGS by documenting the presence of the Y-chromosome. There are certain genetic conditions that are sex-linked, having a mutation on the X-chromosome. Males having only one X-chromosome will have the disease because they express the mutated gene and females having a normal gene on one X-chromosome and mutated one on the other X-chromosome will not express the disease and be thus a carrier of the condition. PGD allows us to determine the sex of the embryo and hence if the baby will have the condition. Additionally, we may directly detect the specific gene mutation with special probes. Some clinics use PGS for the presence of the Y- chromosome for family balancing.

In the IVF laboratory we assess the sperm, oocytes and embryos as they develop in vitro, that is in the Petri dish. With the advent of new molecular based technologies and the ability to perform micro-manipulation of embryos (i.e. safely biopsy) our ability to diagnose abnormalities has expanded dramatically. There are a number of egg/embryo stages where a biopsy may be performed giving us important information. Our IVF lab performs PGD and PGS with day #3 biopsy with embryo transfer on day 5 (i.e. blastocyst stage). We are moving to biopsy of the trophoectoderm (i.e. future placenta) with vitrification of the embryo for future transfer. Vitrification of embryos is an ultra-fast freezing technique that may be better for cryopreservation at the blastocyst stage.

How do we biopsy the embryo?

In general, the embryo has developed to the 6-cell or 8-cell stage by the morning of day 3. The embryo is placed in special media that allows the blastomeres to more easily separate. We use a laser to make a defect in the zona pellucida (i.e. shell around embryo) and then with gentle manipulation we express one of the blastomeres out which will be sent to the lab for genetic testing. The embryos in general tolerate this biopsy well, and will continue to divide to the blastocyst stage (i.e. day 5 embryo) for embryo transfer back into the uterus.

The photo below shows the laser-produced hole in the zona pellucida just prior to removing the blastomere.


Below is a video of the actual biopsy:

 

Blastocyst stage biopsy (i.e., Trophoectoderm (TE) biopsy of 10-30 cells)

The blastocyst stage embryo consists of the inner cell mass (ICM) forming the future embryo, the trophoecoderm cells of the future placenta, and the blastocoel cavity filled with fluid. The photo above shows the ICM on the left side and the TE on the right with the cavity between. There are between 180 and 250 cells at this stage in the embryo. Biopsy of the trophoectoderm would theoretically not harm the embryo. It requires in general that the IVF lab be proficient in the vitrification of embryos (i.e. ultra-fast cryopreservation), which we are at Family Beginnings, PC. The embryos will be vitrified after biopsy for later transfer.

Advantages of TE Biopsy:

  1. Healthiest embryos may have been selected out
  2. Embryo itself not biopsied

Disadvantages:

  1. 40% of embryos do not grow to this stage
  2. Further culture may lead to imprinting disorders
  3. Transfer by day 6 may be a timing issue
  4. Freezing may decrease pregnancy rate
  5. Placental mosaicism (i.e. placenta has more than one cell line)

Picture of TE biopsy
 

Chromosome abnormalities, the early embryo, and PGS

It is remarkable how many conceptions result in aneuploid embryos. Aneuploidy refers to abnormal numbers of chromosomes. The normal complement of chromosomes in 46, with 22 pairs of autosomes and 1 pair of sex chromosomes (i.e. normal male; 46, XY and normal female; 46, XX). The most well known and common aneuploidy is Down’s Syndrome, where a person has an extra chromosome 21. Instead of having 46 chromosomes they have 47. We may see the karyotype shown as 47, XY, +21 in the case of a male or 47, XX, +21 in the case of a female. This may result in miscarriage or the birth of a baby with Down’s syndrome features. Any of the 23 pairs of chromosomes may be affected by aneuploidy. It has been estimated that about 60% of all first trimester pregnancy losses may be aneuploid. Over the past decade or more, embryos from IVF have been evaluated for aneuploidy. It is well accepted that an embryo may be morphologically normal (i.e. 8 cell, grade 1) yet still be chromosomally abnormal. Studies have estimated that for patients doing IVF that are between the ages of 30 and 35 about 40 % of the embryos may be chromosomally abnormal. That number rises to about 60 % when the maternal age is 35 years. PGS has been proposed as potentially useful in patients with repeated IVF failures as well as recurrent pregnancy loss.

While it makes intuitive sense that the pregnancy rates should be higher if only chromosomally normal embryos are transferred, not all studies have borne this out. It is possible that changes in technique for biopsy and day of biopsy (i.e. partial zona dissection versus laser biopsy), stage of embryo biopsy (i.e. day 3 versus day 5), changes in testing modality (i.e. Flourescence In Situ Hybridization (FISH) versus Whole Genome Amplification-WGA- Polymerase Chain Reaction- PCR) may all contribute to the overall pregnancy rates. Well-controlled studies of sufficient power using optimal techniques may give definitive answers regarding the ultimate utility. In 2013, it seems that more data support the use of PGS with WGA-PCR to improve implantation rates and pregnancy rates in patients with increased risk for aneuploidy mentioned above. WGA-PCR is the current standard of treatment.

Our practice is skilled in the day 5 trophoectoderm (TE) biopsy and we offer it to our patients doing PGS. We biopsy the embryo TE, which is essentially the placenta, without risk of damaging the inner cell mass (i.e. future embryo) and either transfer the embryos on day 6, or cryopreserve the embryos for transfer at a later date. We feel that the data that has been published in the scientific literature increasingly supports this stage biopsy. The pregnancy rates are significantly higher.

Given the poor correlation of embryo morphology to predict aneuploidy, PGS represents a significant improvement. The information below shows an example of how difficult it is to predict which embryos are normal. This is an actual embryo lab report that shows how the embryos looked on day 3 and on day 5. On day 3, many clinics would transfer embryos that are from 4 to 8 or 9 cells and from grade 1-3. Grading of embryos is very subjective. These are highlighted in red. Similarly, on day 5 it is common to transfer early blastocyst or blastocyst stage. These are highlighted in red below. As you will see in the PGS report, only the embryo highlighted in blue is normal.

More and more patients are having Non-Invasive Prenatal Testing of maternal serum for aneuploidy. This is a real advancement for pregnant patients to identify a pregnancy with a fetal chromosome abnormality. In the past, we have used blood tests like the triple screen, ultrasound exams and the very invasive amniocentesis in the second trimester. When these tests are abnormal, the couple must consider pregnancy termination or allowing the pregnancy to proceed. PGS seem so much better. The diagnosis is made before implantation sparing a couple having to consider termination of a pregnancy in the late 1st or second trimester.

Sex Selection and PGD/PGS

By determining the embryo chromosome complement the sex of the embryo can be determined. Family balancing or sex-selection are terms used to describe the determination of the embryo’s sex. Many reproductive medicine specialists feel uncomfortable with doing PGS for sex determination as the sole purpose without a medical indication (i.e. sex linked condition like Duchenne’s Muscular Dystrophy). Many consider it a type of sex discrimination where the unwanted sexed embryo would be discarded. Some have agreed to do PGS where the sex of the embryo is known and transferred only if the parents agree to transfer the other embryos at a later date or donate them to another couple. As you can tell, this topic raises all sorts of moral and ethical issues.

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